title: Simvastatin enhances protection against Listeria monocytogenes infection in mice by counteracting Listeria-induced phagosomal escape.
abstract: Statins are well-known cholesterol lowering drugs targeting HMG-CoA-reductase, reducing the risk of coronary disorders and hypercholesterolemia. Statins are also involved in immunomodulation, which might influence the outcome of bacterial infection. Hence, a possible effect of statin treatment on Listeriosis was explored in mice. Statin treatment prior to subsequent L. monocytogenes infection strikingly reduced bacterial burden in liver and spleen (up to 100-fold) and reduced histopathological lesions. Statin-treatment in infected macrophages resulted in increased IL-12p40 and TNF-α and up to 4-fold reduced bacterial burden within 6 hours post infection, demonstrating a direct effect of statins on limiting bacterial growth in macrophages. Bacterial uptake was normal investigated in microbeads and GFP-expressing Listeria experiments by confocal microscopy. However, intracellular membrane-bound cholesterol level was decreased, as analyzed by cholesterol-dependent filipin staining and cellular lipid extraction. Mevalonate supplementation restored statin-inhibited cholesterol biosynthesis and reverted bacterial growth in Listeria monocytogenes but not in listeriolysin O (LLO)-deficient Listeria. Together, these results suggest that statin pretreatment increases protection against L. monocytogenes infection by reducing membrane cholesterol in macrophages and thereby preventing effectivity of the cholesterol-dependent LLO-mediated phagosomal escape of bacteria.
authors.affiliation: International Centre for Genetic Engineering & Biotechnology (ICGEB), Cape Town Component and Institute of Infectious Diseases and Molecular Medicine (IIDMM), Division of Immunology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Suraj P
authors.initials: SP
authors.lastname: Parihar
authors.forename: Reto
authors.initials: R
authors.lastname: Guler
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Lang
authors.forename: Harukazu
authors.initials: H
authors.lastname: Suzuki
authors.forename: A David
authors.initials: AD
authors.lastname: Marais
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006460:Hemolysin Proteins / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D008089:Listeria monocytogenes / Q000187:drug effects* / Q000378:metabolism; D008088:Listeriosis / Q000188:drug therapy / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000187:drug effects; D010588:Phagosomes / Q000187:drug effects* / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D053762:Interleukin-12 Subunit p40; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D019821:Simvastatin; C038705:hlyA protein, Listeria monocytogenes